Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 52c, Josef Möller Haus, 6020 Innsbruck, Austria.
Int J Pharm. 2012 May 30;428(1-2):164-70. doi: 10.1016/j.ijpharm.2012.02.044. Epub 2012 Mar 5.
The purpose of this study was to develop thiolated nanoparticles to enhance the bioavailability for the nasal application of leuprolide. Thiolated chitosan-thioglycolic acid (chitosan-TGA) and unmodified chitosan nanoparticles (NPs) were developed via ionic gelation with tripolyphosphate (TPP). Leuprolide was incorporated during the formulation process of NPs. The thiolated (chitosan-TGA) NPs had a mean size of 252 ± 82 nm, a zeta potential of +10.9 ± 4 mV, and payload of leuprolide was 12 ± 2.8. Sustained release of leuprolide from thiolated NPs was demonstrated over 6h, which might be attributed to inter- and/or intramolecular disulfide formation within the NPs network. Ciliary beat frequency (CBF) study demonstrated that thiolated NPs can be considered as suitable additives for nasal drug delivery systems. Compared to leuprolide solution, unmodified NPs and thiolated NPs provoked increased leuprolide transport through porcine nasal mucosa by 2.0 and 5.2 folds, respectively. The results of a pharmacokinetic study in male Sprague-Dawley rats showed improved transport of leuprolide from thiolated NPs as compared to leuprolide solution. Thiolated NPs had a 6.9-fold increase in area under the curve, more than 4-fold increase in elimination half-life, and a ∼3.8-fold increase in maximum plasma concentration compared to nasal solution alone. The relative nasal bioavailability (versus s.c. injection) of leuprolide thiolated NPs calculated on the basis of AUC((0-6)) was about 19.6% as compared to leuprolide solution 2.8%. The enhanced bioavailability of leuprolide is likely due to facilitated transport by thiolated NPs rather than improved release.
本研究旨在开发巯基化纳米粒子，以提高亮丙瑞林经鼻应用的生物利用度。通过与三聚磷酸（TPP）的离子凝胶作用，制备了巯基化壳聚糖-硫代乙醇酸（壳聚糖-TGA）和未修饰的壳聚糖纳米粒子（NPs）。在 NPs 的配方过程中加入了亮丙瑞林。巯基化（壳聚糖-TGA）NPs 的平均粒径为 252±82nm，zeta 电位为+10.9±4mV，亮丙瑞林的载药量为 12±2.8。巯基化 NPs 表现出亮丙瑞林的持续释放超过 6 小时，这可能归因于 NPs 网络内的分子间和/或分子内二硫键的形成。纤毛摆动频率（CBF）研究表明，巯基化 NPs 可以被认为是适合鼻用药物传递系统的添加剂。与亮丙瑞林溶液相比，未修饰的 NPs 和巯基化 NPs 分别使亮丙瑞林通过猪鼻黏膜的转运增加了 2.0 倍和 5.2 倍。在雄性 Sprague-Dawley 大鼠中的药代动力学研究结果表明，与亮丙瑞林溶液相比，亮丙瑞林从巯基化 NPs 的转运得到了改善。与单独的鼻腔溶液相比，巯基化 NPs 的 AUC（0-6）增加了 6.9 倍，消除半衰期增加了 4 倍以上，最大血浆浓度增加了约 3.8 倍。基于 AUC（0-6）计算的亮丙瑞林巯基化 NPs 的相对鼻生物利用度（与 sc 注射相比）约为亮丙瑞林溶液的 19.6%，为 2.8%。亮丙瑞林生物利用度的提高可能是由于巯基化 NPs 促进了转运，而不是改善了释放。
